Stereochemistry and innate immune recognition: (+)‐norbinaltorphimine targets myeloid differentiation protein 2 and inhibits toll‐like receptor 4 signaling
Year: 2019
Type: article
Abstract: ABSTRACT Deregulation of innate immune TLR4 signaling contributes to various diseases including neuropathic pain and drug addiction. Naltrexone is one of the rare TLR4 antagonists with good blood‐brain barrier permeability and showing no stereoselectivity for TLR4. By linking 2 naltrexone units through a rigid pyrrole spacer, the bivalent ligand norbinaltorphimine was formed. Interestingly, (+)‐norbinaltorphimine [(+)‐1] showed ∼25 times better TLR4 antagonist activity than naltrexone in microglial BV‐2 cell line, whereas (–)‐norbinaltorphimine [(–)‐1] lost TLR4 activity. The enantioselectivity of norbinaltorphimine was further confirmed in primary microglia, astrocytes, and macrophages. The activities of meso isomer of norbinaltorphimine and the molecular dynamic simulation results demonstrate that the stereochemistry of (+)‐1 is derived from the (+)‐naltrexone pharmacophore. Moreover, (+)‐1 significantly increased and prolonged morphine analgesia in vivo . The efficacy of (+)‐1 is long lasting. This is the first report showing enantioselective modulation of the innate immune TLR signaling.—Zhang, X., Peng, Y., Grace, P. M., Metcalf, M. D., Kwilasz, A. J., Wang, Y., Zhang, T., Wu, S., Selfridge, B. R., Portoghese, P. S., Rice, K. C., Watkins, L. R., Hutchinson, M. R., Wang, X. Stereochemistry and innate immune recognition: (+)‐norbinaltorphimine targets myeloid differentiation protein 2 and inhibits toll‐like receptor 4 signaling. FASEB J. 33,9577‐9587 (2019). www.fasebj.org
Source: The FASEB Journal
Institutions: Chinese Academy of Sciences, Changchun Institute of Applied Chemistry, University of Chinese Academy of Sciences, State Key Laboratory of Pharmaceutical Biotechnology, Nanjing University, Chinese Academy of Agricultural Sciences, Institute of Special Animal and Plant Sciences, University of Colorado Boulder, University of Minnesota, University of Minnesota System, National Institute on Drug Abuse, National Institute on Alcohol Abuse and Alcoholism, Australian Research Council, ARC Centre for Nanoscale BioPhotonics, The University of Adelaide, University of Science and Technology of China
Language: English
Subfield: Immunology
Field: Immunology and Microbiology
Domain: Life Sciences
Open Access status: green
Funders: Natural Science Foundation of Jilin Province, National Natural Science Foundation of China, Chinese Academy of Sciences, Chinese Academy of Agricultural Sciences, Nanjing University, State Key Laboratory of Pharmaceutical Biotechnology, National Institutes of Health, National Key Research and Development Program of China, National Institute of Dental and Craniofacial Research, Central Public-interest Scientific Institution Basal Research Fund, Chinese Academy of Fishery Sciences
OpenAlex ID: W2948449456